1. Field of the Invention
The invention relates to a preparation useful for, and a method for the prophylactic treatment of women post-childbirth in order to avoid immunization and antibody production, which could induce NAIT and fetal/neonatal bleeding in subsequent pregnancies.
2. Background of the Invention
Neonatal Alloimmune Thrombocytopenic Purpura. (NAITP)
Two percent of Caucasians are homozygous for human platelet antigen (HPA) 1b. The HPA 1a antigen is a potent immunogen and ten percent of pregnant HPA 1a negative women make antibodies to the HPA 1a antigen after immunization with their fetus' HPA 1a positive platelets. Most of these women have the major histocompatibility antigen HLA-DRB3*0101, but there are examples of women with other HLA DR antigens making the antibodies. The immunization can take place early in the first pregnancy making the fetus thrombocytopenic as early as the 16-20th week of gestation. Intracranial hemorrhage may be fatal, or the fetus can survive with neurological sequels. Fetal alloimmune thrombocytopenia is reported to be present in 1:1000-2000 pregnancies.
Most of the studies reporting frequencies of anti-HPA 1a antibodies have been done retrospectively in women giving birth to thrombocytopenic babies with symptoms of impaired hemostasis. Recently a prospective study of 100 448 pregnant women showed a frequency of HPA 1bb of 2.1%. 10,6% of the women at risk had anti-HPA 1a antibodies and 55 babies had severe thrombocytopenia.
At present there is no general agreement about how to manage the follow-up of the pregnant women with anti-HPA 1a antibodies in order to reduce the risk for bleeding in the fetus/newborn. There is no reliable prenatal parameter to predict which fetuses that are susceptible to life-threatening thrombocytopenia and therefore need closer follow-up or intervention.
In order to approach the questions related to predictable tests for thrombocytopenia and management of the babies to reduce the risk of bleeding, we undertook a prospective investigation of samples from pregnant women referred to our laboratory at the Departments for immunology and transfusion medicine, University Hospital og Northern Norway and Ullev{dot over (a)}l University Hospital, for Rhesus D (RhD) testing.
Until now, the general opinion was that immunization with HPA 1a antigen took place during the first non-compatible pregnancy. Our research has disclosed, however, that in 70-80% of those women with antibodies to HPA 1a, immunization occurs in association with delivery, as antibodies can be detected 6 weeks post partum but not at the time of delivery. This is a very interesting observation, and shows that the time for immunization in NAIT is very similar to that seen in haemolytic disease of the newborn (HDN), contrary to the currently held belief in the art.
Hemolytic Disease of the Newborn (HDN).
A Rhesus D (RhD) negative woman with an RhD positive foetus, can make antibodies against the erythrocytes of her child if red cells enter her circulation. Her antibodies of the IgG class can transfer the placental barrier and destroy the red cells of the foetus. Hemolysis and anemia are the most common results of such antibody transfer, but the most feared complications are hydrops foetalis and death. In HDN, the immunization takes place when the first child is born, and antibodies to Rh(D) can be detected after termination of the pregnancy. Antibodies are not a problem in the first pregnancy, but may affect the next non-compatible child.
Today it is possible to prevent the generation of anti-Rh(D) antibodies in association with pregnancy. Within 72 hours after delivery, the woman is given an intramuscular injection of antibodies to the antigen, namely anti-Rh(D). The accepted explanation for the effect is that such antibodies will destroy or remove the fetal red cells that have passed into the circulation of the mother, and prevent immunization and the formation of antibodies to the Rh(D) antigen.
The antibody preparation is an IgG concentrate made from the plasma of individuals with anti-Rh(D) in their circulation. Normal individuals may have anti-Rh(D) as a consequence of insufficient prophylaxis with anti-Rh(D) in D-negative pregnant women, transfusion of Rh(D) positive blood to Rh(D) negative recipients, or as a result of active immunizations. “Rhesogamma P<<ZLB Behring>>” is a human immunoglobulin containing anti-D for prevention of HDN. 1.5 ml of the preparation contains 1500 IE (200 microgram) of anti-D, which makes up one therapeutic dose. The total amount of IgG in one dose is 255 mg. Ten doses are sold for the price of 3200 NOK.
A prerequisite for an efficient treatment is that the prophylaxis is given before the immune response is established in the mother. This is the case in HDN, as the immunization and antibody production takes place subsequent to the delivery of the first child. The treatment is very efficient, and HDN due to anti-D is seldom seen today.
Current Treatment of Nait
At present, there is no prophylactic treatment for NAIT as is the case with HDN. Newborns with NAIT are treated with platelet transfusions or intravenous injections of gamma globulins after birth. If a woman delivers a child with severe NAIT, she may herself be treated with high dose intravenous IgG and/or steroids in her next pregnancy. In particular cases, the child may be transfused with compatible platelets several times during the second half of the pregnancy. This procedure is associated with a high mortality rate, about 1% in each puncture. These treatment modalities are only eligible when the woman has given birth to a thrombocytopenic child in a previous pregnancy. So, the first child is born without any kind of precautionary action. Other postnatal treatment may anyhow come too late, as the damage to the child may occur during delivery or shortly after.